Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder caused by genetic defects in perforin (FHL type 2, or FHL2) or other proteins in the granule exocytosis pathway (Stepp et al. (1999) Science 286(5446):1957-1959; Brisse et al. (2014) Cytokine Growth Factor Rev., S1359-6101(14)00129-4). Due to the absence of immune-mediated cytotoxicity in these patients, viral infections and other inflammatory stimuli trigger an ineffective but hyperactive immune response that rapidly leads to fatal immunopathology, described clinically as hemophagocytic syndrome (Janka et al. (2014) Blood Rev., 28(4):135-142). Hemophagocytic lymphohistiocytosis (HLH) manifests as a “cytokine storm” with elevated inflammatory cytokines, particularly IFNγ, followed by multi-organ failure, pan-cytopenia, and ultimately death. The difficulty in treating FHL and related hemophagocytic syndromes stems from both the lack of effective therapies and incomplete understanding of the underlying pathophysiology.
Studies of the FHL2 murine model, in which lymphocytic choriomeningitis virus (LCMV) infection of perforin-deficient (Prf1−/−) mice induces disease, demonstrate that pathologic inflammation is driven by an excess of IFNγ-producing LCMV-specific CD8+ T cells (Jordan et al. (2004) Blood 104(3):735-743; Lykens et al. (2011) Blood 118(3):618-626; Matloubian et al. (1999) J. Virol., 73(3):2527-2536). It is thought that the inability of these CD8+ T-cells to kill their targets leads to an over stimulation of these cells by antigen-presenting cells (APCs), and the resultant elevated IFNγ and clinical syndrome. While this overactive T cell response is attributed to excess antigen stimulation through the T cell receptor (TCR) (Terrell et al. (2013) Blood 121(26):5184-5191), data has also shown that non-TCR, MyD88-dependent signaling pathways may be equally important (Krebs et al. (2011) Blood 117(24):6582-6588). Furthermore, the majority of FHL patients do not develop hemophagocytic syndrome until after several months of age (Jessen et al. (2013) Front. Immunol., 4:448), long after they have encountered antigenic pathogens in the environment, consistent with a requirement for additional signals beyond antigen to induce the hyperinflammatory immune response. Improved methods of treating and/or preventing HLH are needed.